WO2009129224A1 - Inhibitors of protein phosphatase-1 and uses thereof - Google Patents
Inhibitors of protein phosphatase-1 and uses thereof Download PDFInfo
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- WO2009129224A1 WO2009129224A1 PCT/US2009/040495 US2009040495W WO2009129224A1 WO 2009129224 A1 WO2009129224 A1 WO 2009129224A1 US 2009040495 W US2009040495 W US 2009040495W WO 2009129224 A1 WO2009129224 A1 WO 2009129224A1
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- 0 CC[C@](C)C(*C(C(C)OC(C1=C(CCCC2=C[C@@](C3)C=CC=C3[N+]([O-])=O)C2=C*c2ccccc12)=O)=O)=O Chemical compound CC[C@](C)C(*C(C(C)OC(C1=C(CCCC2=C[C@@](C3)C=CC=C3[N+]([O-])=O)C2=C*c2ccccc12)=O)=O)=O 0.000 description 5
- OCDQSQCQUUTWIK-UHFFFAOYSA-N NC(CN1CC2C=CC=CC2CC1)=O Chemical compound NC(CN1CC2C=CC=CC2CC1)=O OCDQSQCQUUTWIK-UHFFFAOYSA-N 0.000 description 2
- GKWNCOPDPUIGAG-UHFFFAOYSA-N CCC(C1C=CC(OC)=CC1)C(CNCC1)c2c1cccc2 Chemical compound CCC(C1C=CC(OC)=CC1)C(CNCC1)c2c1cccc2 GKWNCOPDPUIGAG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the present invention relates to inhibitors of Protein Phosphatase- 1 , and medical uses of such inhibitors. More specifically, a class of compounds is provided that inhibit PP-I. Further, methods o use PP-I inhibitors for treating HIV-I infections are described.
- Compounds are provided that inhibit HIV-I transcription. Without being bound by any theory, it is believed that the compounds inhibit interaction between PPl and an HIV-I Tat, thereby inhibiting HIV-I transcription. The compounds have been shown to inhibit HIV-I transcription in living cells. The compounds are thus useful for treating or preventing HIV-I infections.
- n 1 or 2;
- Ar is phenyl or thienyl, and is optionally substituted; each R 1 is independently R 6 , C(O)R 6 , C(O)-OR 6 , or C(O) N(R 6 ) 2 ;
- R 2 is H or optionally substituted C1-C6 alkyl, or a group of formula -C(O)NH-R 1 ;
- R 3 is independently at each occurrence selected from halo, NO 2 , CN, R, OR, NR 2 ;
- Z is O or NR 5 ;
- R 5 is R 6 or C(O)R 6 ;
- R 6 is independently at each occurrence selected from H, C1-C6 alkyl, C5-C6 aryl, and (C5-C6-aryl)-Cl-C6 alkyl, where each alkyl and aryl is optionally substituted; provided that n is 2 when Z is 0 and Ar represents para-halophenyl; or a pharmaceutically acceptable salt thereof.
- compositions that include at least one compound of formula (I) and other compounds described herein are admixed with a pharmaceutically acceptable excipient.
- a pharmaceutically acceptable excipient for manufacture of a medicament, especially a medicament for the treatment of HIV infected subjects are provided.
- methods are provided to treat or prevent an HIV-I infection by administering to a subject in need thereof an effective amount of a compound of formula (I) and other compounds described herein.
- the methods include various routes of administration for the compounds of formula (I) and other compounds described herein as well as use of a compound of formula (I) in combination with other therapeutic agents effective for the treatment or prevention of HIV-I infections.
- alkyl straight-chain, branched-chain and cyclic monovalent hydrocarbyl radicals, and combinations of these, which contain only C and H when they are unsubstituted. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentyl ethyl, 2-propenyl, 3-butynyl, and the like.
- the total number of carbon atoms in each such group is sometimes described herein, e.g., when the group can contain up to ten carbon atoms it can be represented as 1-10 C or as Cl-ClO or Cl-10.
- the numbers describing the group represent the sum of the number of carbon atoms in the group plus the number of such heteroatoms that are included as replacements for carbon atoms in the ring or chain being described.
- the alkyl, alkenyl and alkynyl substituents of the invention contain 1-10 C(alkyl) or 2-10 C (alkenyl or alkynyl). Preferably they contain 1-8 C (alkyl) or 2-8 C (alkenyl or alkynyl).
- a single group can include more than one type of multiple bond, or more than one multiple bond; such groups are included within the definition of the term "alkenyl” when they contain at least one carbon- carbon double bond, and are included within the term "alkynyl” when they contain at least one carbon carbon triple bond.
- Alkyl, alkenyl and alkynyl groups are often substituted to the extent that such substitution makes sense chemically.
- Alkyl, alkenyl and alkynyl groups can also be substituted by C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl or C5-C10 heteroaryl, each of which can be substituted by the substituents that are appropriate for the particular group.
- Heteroalkyl “heteroalkenyl”, and “heteroalkynyl” and the like are defined similarly to the corresponding hydrocarbyl (alkyl, alkenyl and alkynyl) groups, but the 'hetero' terms refer to groups that contain 1-30, S or N heteroatoms or combinations thereof within the backbone residue; thus at least one carbon atom of a corresponding alkyl, alkenyl, or alkynyl group is replaced by one of the specified heteroatoms to form a heteroalkyl, heteroalkenyl, or heteroalkynyl group.
- heteroforms of alkyl, alkenyl and alkynyl groups are generally the same as for the corresponding hydrocarbyl groups, and the substituents that may be present on the heteroforms are the same as those described above for the hydrocarbyl groups.
- substituents that may be present on the heteroforms are the same as those described above for the hydrocarbyl groups.
- such groups do not include more than two contiguous heteroatoms except where an oxo group is present on N or S as in a nitro or sulfonyl group.
- alkyl as used herein includes cycloalkyl and cycloalkylalkyl groups
- cycloalkyl may be used herein to describe a carbocyclic non-aromatic group that is connected via a ring carbon atom
- cycloalkylalkyl may be used to describe a carbocyclic non-aromatic group that is connected to the molecule through an alkyl linker.
- heterocyclyl may be used to describe a non-aromatic cyclic group that contains at least one heteroatom as a ring member and that is connected to the molecule via a ring atom, which may be C or N; and “heterocyclylalkyl” may be used to describe such a group that is connected to another molecule through a linker.
- the sizes and substituents that are suitable for the cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl groups are the same as those described above for alkyl groups. As used herein, these terms also include rings that contain a double bond or two, as long as the ring is not aromatic.
- acyl encompasses groups comprising an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical attached at one of the two available valence positions of a carbonyl carbon atom
- heteroacyl refers to the corresponding groups wherein at least one carbon other than the carbonyl carbon has been replaced by a heteroatom chosen from N, O and S.
- Acyl and heteroacyl groups are bonded to any group or molecule to which they are attached through the open valence of the carbonyl carbon atom. Typically, they are C1-C8 acyl groups, which include formyl, acetyl, pivaloyl, and benzoyl, and C2-C8 heteroacyl groups, which include methoxyacetyl, ethoxycarbonyl, and 4-pyridinoyI.
- the hydrocarbyl groups, aryl groups, and heteroforms of such groups that comprise an acyl or heteroacyl group can be substituted with the substituents described herein as generally suitable substituents for each of the corresponding component of the acyl or heteroacyl group.
- Aromatic moiety or "aryl” moiety refers to a monocyclic or fused bicyclic moiety having the well-known characteristics of aromaticity; examples include phenyl and naphthyl.
- 'Aryl 1 can include aromatic ring systems containing only carbon as well as aromatic ring systems containing one or more heteroatoms (O, N or S) as ring members.
- heteroatoms O, N or S
- heteroaryl refer to such monocyclic or fused bicyclic ring systems which contain as ring members one or more heteroatoms selected from O, S and N. The inclusion of a heteroatom permits aromaticity in 5-membered rings as well as 6-membered rings.
- Typical heteroaromatic systems include monocyclic C5-C6 aromatic groups such as pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, and imidazolyl and the fused bicyclic moieties formed by fusing one of these monocyclic groups with a phenyl ring or with any of the heteroaromatic monocyclic groups to form a C8-C10 bicyclic group such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, quinazolinyl, quinoxalinyl, cinnolinyl, and the like.
- monocyclic C5-C6 aromatic groups such as pyridyl, pyrimidy
- any mono cyclic or fused ring bicyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system is included in this definition. It also includes bicyclic groups where at least the ring which is directly attached to the remainder of the molecule has the characteristics of aromaticity.
- the ring systems contain 5-12 ring member atoms.
- the monocyclic heteroaryls contain 5-6 ring members, and the bicyclic heteroaryls contain 8-10 ring members.
- Aryl and heteroaryl moieties may be substituted with a variety of substituents including C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12 aryl, C1-C8 acyl, and heteroforms of these, each of which can itself be further substituted; other substituents for aryl and heteroaryl moieties include halo, OR, NR 2 , SR, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRCONR 2 , NRCOOR, NRCOR, CN, COOR, CONR 2 , OOCR, COR, and NO 2 , wherein each R is independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, C5-C10
- an arylalkyl substituent may be substituted on the aryl portion with substituents described herein as typical for aryl groups, and it may be further substituted on the alkyl portion with substituents described herein as typical or suitable for alkyl groups.
- arylalkyl and “heteroarylalkyl” refer to aromatic and heteroaromatic ring systems which are bonded to their attachment point through a linking group such as an alkylene, including substituted or unsubstituted, saturated or unsaturated, cyclic or acyclic linkers.
- the linker is C1-C8 alkyl or a hetero form thereof.
- These linkers may also include a carbonyl group, thus making them able to provide substituents as an acyl or heteroacyl moiety.
- An aryl or heteroaryl ring in an arylalkyl or heteroarylalkyl group may be substituted with the same substituents described above for aryl groups.
- an arylalkyl group includes a phenyl ring optionally substituted with the groups defined above for aryl groups and a C1-C4 alkylene that is unsubstituted or is substituted with one or two C1-C4 alkyl groups or heteroalkyl groups, where the alkyl or heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane, dioxolane, or oxacyclopentane.
- a heteroarylalkyl group preferably includes a C5-C6 monocyclic heteroaryl group that is optionally substituted with the groups described above as substituents typical on aryl groups and a C1-C4 alkylene that is unsubstituted or is substituted with one or two C1-C4 alkyl groups or heteroalkyl groups, or it includes an optionally substituted phenyl ring or C5-C6 monocyclic heteroaryl and a C1-C4 heteroalkylene that is unsubstituted or is substituted with one or two C1-C4 alkyl or heteroalkyl groups, where the alkyl or heteroalkyl groups can optionally cyclize to form a ring such as cyclopropane, dioxolane, or oxacyclopentane.
- substituents may be on either the alkyl or heteroalkyl portion or on the aryl or heteroaryl portion of the group.
- the substituents optionally present on the alkyl or heteroalkyl portion are the same as those described above for alkyl groups generally; the substituents optionally present on the aryl or heteroaryl portion are the same as those described above for aryl groups generally.
- Arylalkyl groups as used herein are hydrocarbyl groups if they are unsubstituted, and are described by the total number of carbon atoms in the ring and alkylene or similar linker.
- a benzyl group is a C7-arylalkyl group
- phenyl ethyl is a C8-arylalkyl.
- Heteroarylalkyl refers to a moiety comprising an aryl group that is attached through a linking group, and differs from “arylalkyl” in that at least one ring atom of the aryl moiety or one atom in the linking group is a heteroatom selected from N, O and S.
- the heteroarylalkyl groups are described herein according to the total number of atoms in the ring and linker combined, and they include aryl groups linked through a heteroalkyl linker; heteroaryl groups linked through a hydrocarbyl linker such as an alkylene; and heteroaryl groups linked through a heteroalkyl linker.
- C7-heteroarylalkyl would include pyridylmethyl, phenoxy, and N-pyrrolylmethoxy.
- Alkylene refers to a divalent hydrocarbyl group; because it is divalent, it can link two other groups together. Typically it refers to -(CHb) n - where n is 1 -8 and preferably n is 1-4, though where specified, an alkylene can also be substituted by other groups, and can be of other lengths, and the open valences need not be at opposite ends of a chain. Thus - CH(Me)- and -C(Me) 2 - may also be referred to as alkylenes, as can a cyclic group such as cyclopropan-l,l-diyl. Where an alkylene group is substituted, the substituents include those typically present on alkyl groups as described herein.
- any alkyl, alkenyl, alkynyl, acyl, or aryl or arylalkyl group or any heteroform of one of these groups that is contained in a substituent may itself optionally be substituted by additional substituents.
- the nature of these substituents is similar to those recited with regard to the primary substituents themselves if the substituents are not otherwise described.
- R7 is alkyl
- this alkyl may optionally be substituted by the remaining substituents listed as embodiments for R7 where this makes chemical sense, and where this does not undermine the size limit provided for the alkyl per se; e.g., alkyl substituted by alkyl or by alkenyl would simply extend the upper limit of carbon atoms for these embodiments, and is not included.
- each such alkyl, alkenyl, alkynyl, acyl, or aryl group may be substituted with a number of substituents according to its available valences; in particular, any of these groups may be substituted with fluorine atoms at any or all of its available valences, for example.
- the number is preferably 0-2.
- Heteroform refers to a derivative of a group such as an alkyl, aryl, or acyl, wherein at least one carbon atom of the designated carbocyclic group has been replaced by a heteroatom selected from N, O and S.
- the hetero forms of alkyl, alkenyl, alkynyl, acyl, aryl, and arylalkyl are heteroalkyl, heteroalkenyl, heteroalkynyl, heteroacyl, heteroaryl, and heteroarylalkyl, respectively. It is understood that no more than two N, O or S atoms are ordinarily connected sequentially, except where an oxo group is attached to N or S to form a nitro or sulfonyl group.
- the group takes up two available valences, so the total number of substituents that may be included is reduced according to the number of available valences.
- Halo as used herein includes fluoro, chloro, bromo and iodo. Fluoro and chloro are often preferred.
- Haloalkyl as used herein includes alkyl groups having one or more halogen substituents. Examples include trifluoromethyl, 2,2,2-trifIuoroethyl, 2-chloroethyl, 2-fluoroethyl, and the like.
- Amino refers to NH 2 , but where an amino is described as “substituted” or “optionally substituted”, the term includes NR'R" wherein each R' and R" is independently H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl group or a heteroform of one of these groups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkyl groups or heteroforms of one of these groups is optionally substituted with the substituents described herein as suitable for the corresponding group.
- R' and R" are linked together to form a 3-8 membered ring which may be saturated, unsaturated or aromatic and which contains 1-3 heteroatoms independently selected from N, O and S as ring members, and which is optionally substituted with the substituents described as suitable for alkyl groups or, if NR 1 R" is an aromatic group, it is optionally substituted with the substituents described as typical for heteroaryl groups.
- the invention includes each individual isomer as well as mixtures of isomers. Where a chiral center is present, the invention includes each individual enantiomer at the chiral center as well as mixtures of enantiomers, including racemic mixtures.
- the invention provides compounds that inhibit PP 1.
- the compounds are of formula (I):
- n 1 or 2;
- Ar is phenyl or thienyl, and is optionally substituted; each R 1 is independently R 6 , C(O)R 6 , C(O)-OR 6 , or C(O) N(R 6 ) 2 ;
- R 2 is H or optionally substituted C1-C6 alkyl, or a group of formula -C(O)NH-R 1 ;
- R 3 is independently at each occurrence selected from halo, NO 2 , CN, R, OR, NR 2 ;
- Z is O or NR 5 ;
- R 5 is R 6 or C(O)R 6 ;
- R 6 is independently at each occurrence selected from H, C1-C6 alkyl, C5-C6 aryl, and (C5-C6-aryl)-Cl-C6 alkyl, where each alkyl and aryl is optionally substituted; provided that n is 2 when Z is O and Ar represents para-halophenyl; or a pharmaceutically acceptable salt thereof.
- Z is NR 5 .
- R 5 is sometimes H and it is sometimes -C(O)R 1 , where R' is a C1-C4 alkyl or C1-C4 haloalkyl.
- Z is O or NH; preferably Z is O.
- Ar is phenyl, which is optionally substituted.
- Ar is not 4-halophenyl.
- Ar is thienyl, which can be substituted. Thienyl can be attached at either position 2 or position 3 of the thiophene ring.
- Ar is 2- thienyl, and is optionally substituted.
- Ar is optionally substituted 3- thienyl.
- n is 1. In some embodiments, n is 2.
- R 2 is H or C1-C4 alkyl or C1-C4 haloalkyl.
- R 2 is H, methyl or ethyl.
- n is O. In other embodiments, m is 1-2.
- At least one R 3 is halo, CI-C4 alkyl, or Cl- C4 haloalkyl.
- p is O. hi other embodiments, p is 1-2.
- R 4 is 0, C1-C4 alkyl, or C1-C4 haloalkyl.
- R 1 is an optionally substituted C1-C6 alkyl.
- R 1 is C(O)R 6 .
- R 1 is C(O)NHR 6 .
- the compounds of formula (I) readily form acid addition salts.
- the compound of formula (I) is an acid addition salt.
- the acid addition salt is a pharmaceutically acceptable salt.
- IC-50 effective concentration
- Table 1 provides some data showing efficacy of selected compounds for inhibition of Tat-induced transcription of HIV-I in two cell lines. It also provides a qualitative assessment of the toxicity of the compounds in those cell lines, and shows that one compound (Compound A) inhibited HIV-I replication by 50% at 10 ⁇ M.
- the compounds described herein can be prepared using well-known reactions, starting from available starting materials such as l,2,3,4-tetrahydroacridine-9-carboxylic acid as summarized in Scheme 1. This acid can readily be converted to an ester or an amide to provide compounds wherein Z is O or N, respectively, using standard conditions that are well known in the art. The wide array of available alcohols and amines enables one to synthesize many compounds with various R 1 and R 2 groups incorporated.
- a base such as potassium tert-butoxide in a polar, aprotic solvent such as DMSO, DMF, DME, or THF, or in a non- nucleophilic protic solvent such as t-butanol.
- the compounds described herein are shown to be effective inhibitors of replication of HIV-I in cell lines. Accordingly, the compounds are useful to treat or prevent HIV -1 infections in animals, including humans.
- Use of the compounds includes administering to a subject in need thereof an effective amount of a compound of formula I or other compounds described herein or pharmaceutical compositions thereof.
- Pharmaceutical compositions comprising an effective amount of at least one compound of Formula I or other compounds described herein are provided and include at least one compound of Formula I or other compounds described herein admixed with at least one pharmaceutically acceptable excipient.
- the method includes identifying a subject in need of such treatment.
- the compounds described herein may be used for the manufacture of a medicament, and for the manufacture of a medicament for the treatment of HIV-I .
- the compounds of Formulas I and other compounds described herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. Methods and formulations for each of these routes of administration are within the knowledge and expertise of a person of ordinary skill in the art.
- the compounds of the present invention may be used in combinations with one or more agents useful in the prevention or treatment of HIV.
- agents include: (1) nucleotide reverse transcriptase inhibitor such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine todoxil, etc.; (2) non-nucleotide reverse transcriptase inhibitor (including an agent having anti- oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, etc.; and (3) protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, palinavir, lasinavir, etc.
- combinations of compounds of Formulas I and other compounds described herein with other HIV agents is not limited to (1), (2), and or (3), but includes in principle, any combination with any pharmaceutical composition useful for the treatment of HIV. Further, in such combination treatments the compounds of the present invention and other HIV agents may be administered separately or in conjunction, as a single composition or as separate compositions. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
- the compounds of Formulas I and other compounds described herein are all used to treat animals, including but not limited to, mice, rats, horses, cattle, sheep, dogs, cats, and monkey.
- the compounds described herein are also effective for use in humans.
- the compounds of Formulas I and other compounds described herein may form hydrates or solvates, which are included in the scope of the claims.
- the compounds of Formulas I and other compounds described herein exist as regioisomers, configurational isomers, conformers, or diasteroisomeric forms, all such forms and various mixtures thereof are included in the generic formulas. It is possible to isolate individual isomers using known separation and purification methods, if desired. For example, when a compound of Formulas I is a racemate, the racemate can be separated into the (S)-compound and (R)-compound by optical resolution. Individual optical isomers and mixtures thereof are included in the scope of the generic formula.
- the compounds of the invention can be used in their neutral form, or as a salt.
- the compounds of formula I and other compounds described herein readily form acid addition salts, and in some embodiments, the acid addition salts are preferable for use in the methods and pharmaceutical compositions of the invention. Formation of such salts is within the ordinary level of skill in the art, and can be achieved by contacting a compound of formula I or other compounds described herein with a suitable acid.
- the salt used can be any stable salt; in some embodiments, the acid is selected to provide a pharmaceutically acceptable salt.
- Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiological acceptable anion, for example, tosylate, methanesulfonate, besylate, acetate, formate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, lactate, and a- glycerophosphate.
- Suitable inorganic salts may also be formed, including hydrochloride, sulfate, bisulfate, phosphate, nitrate, hydrobromide, and the like.
- compositions include a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of Formula I or other compounds described herein.
- the pharmaceutical compositions preferably comprise at least one acceptable diluent or excipient other than water, methanol, ethanol, or DMSO.
- the pharmaceutical composition comprises at least one excipient selected from a buffer, saline, and a mono- or di-saccharide.
- a compound of Formulas I and other compounds described herein may be administered alone or as an admixture with a pharmaceutically acceptable carrier (e.g., solid formulations such as tablets, capsules, granules, powders, etc.; liquid formulations such as syrups, injections, etc.) and may be orally or non-orally administered.
- a pharmaceutically acceptable carrier e.g., solid formulations such as tablets, capsules, granules, powders, etc.; liquid formulations such as syrups, injections, etc.
- non-oral formulations include injections, drops, suppositories, and pessaries.
- an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in singe or multiple doses.
- the dosage level will be about 0.1 to about 100, or from about 0.1 to about 10 mg/kg per day. It will be understood that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound used, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the patient undergoing therapy.
- a compound is administered systemically (e.g., orally) in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly with the food of the patient's diet.
- a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
- the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
- Such compositions and preparations should contain at least 0.1 % of active compound. The percentage of the compositions and preparations may be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
- Tablets, troches, pills, capsules, and the like also may contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
- a liquid carrier such as a vegetable oil or a polyethylene glycol.
- any material used in preparing any unit dosage form is pharmaceutically acceptable and substantially non-toxic in the amounts employed.
- the active compound may be incorporated into sustained-release preparations and devices.
- the active compound also may be administered intravenously or intraperitoneally by infusion or injection.
- Solutions of the active compound or its salts may be prepared in a buffered solution, often phosphate buffered saline, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the compound is sometimes prepared as a polymatrix-containing formulation for such administration (e.g., a liposome or microsome). Liposomes are described for example in U.S. Patent No. 5,703,055 (Feigner, et al.) and Gregoriadis, Liposome Technology vols. I to II (2nd ed. 1993).
- the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient that-are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
- the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the particle size in the case of dispersions or by the use of surfactants.
- the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
- Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
- the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile- filtered solutions.
- the present compounds may be applied in liquid form. Compounds often are administered as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
- Examples of useful dermatological compositions used to deliver compounds to the skin are known (see, e.g., Jacquet, et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith, et al. (U.S. Pat. No. 4,559,157) and Wortman (U.S. Pat. No. 4,820,508).
- Compounds may be formulated with a solid carrier, which can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, or alumina and the like.
- a solid carrier which can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, or alumina and the like.
- Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
- Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
- the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
- Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
- the concentration of the compound in a liquid composition often is from about 0.1 wt% to about 25 wt%, sometimes from about 0.5 wt% to about 10 wt%.
- the concentration in a semi-solid or solid composition such as a gel or a powder often is about 0.1 wt% to about 5 wt%, sometimes about 0.5 wt% to about 2.5 wt%.
- a compound composition may be prepared as a unit dosage form, which is prepared according to conventional techniques known in the pharmaceutical industry. In general terms, such techniques include bringing a compound into association with pharmaceutical carriers) and/or excipient(s) in liquid form or finely divided solid form, or both, and then shaping the product if required.
- the compound composition may be formulated into any dosage form, such as tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas.
- the compositions also may be formulated as suspensions in aqueous, non-aqueous, or mixed media.
- Aqueous suspensions may further contain substances which increase viscosity, including for example, sodium carboxymethylcellulose, sorbitol, and/or dextran.
- the suspension may also contain one or more stabilizers.
- Table 2 Analysis of 262 small molecule compounds for the inhibition of HIV-I transcription in CEM GFP cells. Percent of inhibition is shown. Compounds chosen for further analysis are shown in gray.
- Selected compounds (69 compounds from Table 1 , marked as gray shadow) were further evaluated to determine their IC50s and also cellular toxicity Analysis of these compounds identified number of compounds that were inhibitory (Table 2).
- Table 3 Selected compounds that shown inhibition of HIV-I transcription. Non-toxic compounds with IC50s less than 10 ⁇ M are shown in gray shadow.
- Fig. IA shows an example of inhibition of transcription and measurements of cytotoxicity by the compounds encoded as 1H4, 3C8, 1G3 and 1C7.
- the compounds 1H4 and 3C8 were not toxic and inhibited HIV-I transcription (Fig. IA).
- 1C7 compound potently inhibited HIV-I transcription but also demonstrated a high cytotoxicity (Fig.lA).
- the 1G3 compounds was neither inhibitory nor toxic (Fig.1 A).
- Compounds 1H4, 3C8, and 1G3 were further evaluated in 293T cells transfected with Tat-expressmg vector, HIV-I LTR-LacZ reporter and CMV-EGFP reporter. Inhibitory properties of these compounds were evaluated using 293T cells transfected with Tat-expressing vector, HIV-I LTR-LacZ reporter and CMV-EGFP reporter (Ammosova et al., 2005a). 293T cells were transfected with lipofectamine and then treated with each of the selected compounds for 18 hours. Then the cells were lysed and GFP and ⁇ -galactosidase activity was determined as we previously described (Ammosova et al., 2005a).
- the 1C7 compound did not inhibit Tat-induced HIV-I transcription in this system (not shown).
- Neither of the compounds was cytotoxic as determined by LDH assay (not shown).
- HIV-I replication is inhibited by a small molecular mimetic of QVCF peptide.
- the 1H4 compound was evaluated to determine whether it could inhibit HIV-I replication.
- MT4 cells were infected with recombinant pNL4-3 HIV-I and treated with different concentrations of 1H4 compound and as a control 1G3 compound.
- the 1H4 compound inhibited HIV-I replication at lO ⁇ M or 25 ⁇ M concentrations (Fig. 2).
- the 1G3 compound did not inhibit HIV-I replication but in contrast induced it by about 2-fold (Fig. 2).
- the 1H4 compound inhibits HFV-I replication.
- the 1H4 compound docks to the PPl and inhibits Tat-PPl interaction in vitro.
- a typical regulatory subunit of PPl contains at least one RVxF motif, which directly interacts with a hydrophobic pocket on the surface of PPl.
- Interaction of the 1H4 with PPl was analyzed by its docking using computer modeling. Docking shows that 1H4 occupies the hydrophobic sites of the RVTF peptide but also interacts with PPl through additional binding sites.
- the 1H4 compound was used to create a second library of compounds that would have similar backbone as 1H4.
- This second library contained 143 compounds. These compounds were analyzed for the inhibition of HIV-I transcription and toxicity in CEM T-cells and 293T cells similar as described above for the analysis of the first library Results shown in Table 4 show that several compounds were inhibitory. Two compounds were chosen, 1E07 (T5236177) and 2F02 (T5430740) (shaded), because there were not toxic in the propidium iodide uptake assay and inhibited HIV-I transcription both in CEM and 293T cells.
- Table 4 Selected compounds from the lH4-based library that shown inhibition of HIV-I transc ⁇ ption.
Abstract
Description
Claims
Priority Applications (5)
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RU2010146147/04A RU2527561C2 (en) | 2008-04-16 | 2009-04-14 | Protein phosphatase-1 inhibitors and using them |
EP09732857.9A EP2265117B1 (en) | 2008-04-16 | 2009-04-14 | Inhibitors of protein phosphatase-1 and uses thereof |
CA2721203A CA2721203C (en) | 2008-04-16 | 2009-04-14 | Inhibitors of protein phosphatase-1 and uses thereof |
UAA201013424A UA110918C2 (en) | 2008-04-16 | 2009-04-14 | Inhibitors of protein phosphatase-1 and their use |
AU2009236303A AU2009236303B2 (en) | 2008-04-16 | 2009-04-14 | Inhibitors of Protein Phosphatase-1 and uses thereof |
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US4556108P | 2008-04-16 | 2008-04-16 | |
US61/045,561 | 2008-04-16 |
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US (1) | US8278326B2 (en) |
EP (1) | EP2265117B1 (en) |
AU (1) | AU2009236303B2 (en) |
CA (1) | CA2721203C (en) |
RU (1) | RU2527561C2 (en) |
UA (1) | UA110918C2 (en) |
WO (1) | WO2009129224A1 (en) |
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CA2881967C (en) * | 2012-08-14 | 2021-02-23 | Howard University | Inhibitors of protein phosphatase-1 and uses thereof |
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JPS61106636A (en) * | 1984-10-31 | 1986-05-24 | Toray Silicone Co Ltd | Silicone rubber sponge composition |
RU2326115C2 (en) * | 2005-11-21 | 2008-06-10 | Ефаг АО | Salts of 1-alkylamino-1-desoxypolyols with 9-oxoacridine-10-acetic acid, medicinal preparations on their base, their use, preventive measures and treatment |
-
2009
- 2009-04-14 CA CA2721203A patent/CA2721203C/en active Active
- 2009-04-14 RU RU2010146147/04A patent/RU2527561C2/en active
- 2009-04-14 WO PCT/US2009/040495 patent/WO2009129224A1/en active Application Filing
- 2009-04-14 UA UAA201013424A patent/UA110918C2/en unknown
- 2009-04-14 EP EP09732857.9A patent/EP2265117B1/en not_active Not-in-force
- 2009-04-14 AU AU2009236303A patent/AU2009236303B2/en not_active Ceased
- 2009-04-15 US US12/424,243 patent/US8278326B2/en active Active
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US4559157A (en) | 1983-04-21 | 1985-12-17 | Creative Products Resource Associates, Ltd. | Cosmetic applicator useful for skin moisturizing |
US4608392A (en) | 1983-08-30 | 1986-08-26 | Societe Anonyme Dite: L'oreal | Method for producing a non greasy protective and emollient film on the skin |
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US6593324B2 (en) * | 2000-03-01 | 2003-07-15 | Orion Corporation | Dervatives of quinoline as alpha-2 antagonists |
US7307083B2 (en) * | 2005-01-27 | 2007-12-11 | Alma Mater Studiorum-Universita'di Bologna | Tetrahydro-acridine and dithiolane derivatives |
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See also references of EP2265117A4 * |
Also Published As
Publication number | Publication date |
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RU2010146147A (en) | 2012-05-27 |
AU2009236303B2 (en) | 2014-12-04 |
CA2721203C (en) | 2016-11-01 |
EP2265117A1 (en) | 2010-12-29 |
US20090264463A1 (en) | 2009-10-22 |
UA110918C2 (en) | 2016-03-10 |
EP2265117A4 (en) | 2012-03-21 |
EP2265117B1 (en) | 2017-06-07 |
RU2527561C2 (en) | 2014-09-10 |
AU2009236303A1 (en) | 2009-10-22 |
CA2721203A1 (en) | 2009-10-22 |
US8278326B2 (en) | 2012-10-02 |
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